QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 23, 2005, 25(8):1889-1893; doi:10.1523/JNEUROSCI.4778-04.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Desai, R. I. Articles by Katz, J. L. Search for Related Content PubMed PubMed Citation Articles by Desai, R. I. Articles by Katz, J. L.

 Previous Article  |  Next Article 

BRIEF COMMUNICATION
Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

Rajeev I. Desai,¹ Theresa A. Kopajtic,¹ Mikhail Koffarnus,¹ Amy Hauck Newman,² and Jonathan L. Katz¹

¹Psychobiology and ²Medicinal Chemistry Sections, Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, National Institutes of Health, Baltimore, Maryland 21224

There is a large unmet medical need for cocaine addiction treatments. Studies have indicated that the dopamine transporter (DAT) is the primary biological target of cocaine, and most drugs that have DAT affinity have behavioral effects like those of cocaine. However, analogs of benztropine have high DAT affinity and behavioral effects that show varying degrees of similarity to cocaine. We now report the discovery that a benztropine analog, JHW007, with high affinity for the DAT does not have cocaine-like behavioral effects and antagonizes the effects of cocaine. JHW007 occupied the DAT in vivo more slowly than did cocaine and had not reached an apparent plateau up to 270 min after injection. The in vivo binding of cocaine to the DAT suggested rate of DAT occupancy as an important contributor to its behavioral effects, and the slow association with the DAT may provide an explanation for JHW007 being relatively devoid of cocaine-like behavioral effects. The antagonism of cocaine suggests that DAT ligands with reduced cocaine-like activity can function as cocaine antagonists and suggests JHW007 as a lead for discovery of cocaine-abuse pharmacotherapeutics.

Key words: cocaine abuse; cocaine antagonist; dopamine transporter; ex vivo binding; JHW007; benztropine analogs

---

Received Nov 23, 2004; revised January 7, 2005; accepted January 8, 2005.

This article has been cited by other articles:

				V. Murthy, T. J. Martin, S. Kim, H. M. L. Davies, and S. R. Childers In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 587 - 595. [Abstract] [Full Text] [PDF]

				C. J. Loland, R. I. Desai, M.-F. Zou, J. Cao, P. Grundt, K. Gerstbrein, H. H. Sitte, A. H. Newman, J. L. Katz, and U. Gether Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors Mol. Pharmacol., March 1, 2008; 73(3): 813 - 823. [Abstract] [Full Text] [PDF]

				A. A. Othman, A. H. Newman, and N. D. Eddington Applicability of the Dopamine and Rate Hypotheses in Explaining the Differences in Behavioral Pharmacology of the Chloro-Benztropine Analogs: Studies Conducted Using Intracerebral Microdialysis and Population Pharmacodynamic Modeling J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 760 - 769. [Abstract] [Full Text] [PDF]

				A. A. Othman, S. A. Syed, A. H. Newman, and N. D. Eddington Transport, Metabolism, and in Vivo Population Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models of Drug Abuse J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 344 - 353. [Abstract] [Full Text] [PDF]

				R. I. Desai, T. A. Kopajtic, D. French, A. H. Newman, and J. L. Katz Relationship between in Vivo Occupancy at the Dopamine Transporter and Behavioral Effects of Cocaine, GBR 12909 [1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and Benztropine Analogs J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 397 - 404. [Abstract] [Full Text] [PDF]

				O. T. Ukairo, C. D. Bondi, A. H. Newman, S. S. Kulkarni, A. P. Kozikowski, S. Pan, and C. K. Surratt Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 575 - 583. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help